The present application is directed to novel antidiabetic compounds.
The causes of Type I and Type II diabetes are still unknown, although both genetic and environmental factors seem to be involved. Type I diabetes (or insulin-dependent diabetes) is an autonomic immune disease in which the responsible autoantigen is still unknown. Patients with Type I diabetes need to take insulin intravenously to survive. Type II diabetes (formerly referred to as non-insulin dependent diabetes) is a metabolic disorder resulting from the body's inability either to make a sufficient amount of insulin or to properly use the insulin that is produced. Insulin secretion and insulin resistance are considered the major metabolic defects, but the precise genetic factors involved remain unknown.
Patients with diabetes usually have one or more of the following defects:                Under-production of insulin by the pancreas        Over-secretion of glucose by the liver        Defects in glucose transporters        Desensitization of insulin receptors        Defects in metabolic breakdown of polysaccharides        
In addition to the IV administration of insulin, currently available medications used for diabetes include 4 classes of oral hypoglycemic agents listed in the following table.
MarketedMechanism ofClassDrugsActionLimitationsSulfonyl-FirstSignals beta cellsDevelopment ofureasgeneration: 2to release moreresistanceSecondinsulinHypoglycemiageneration: 3Bi-MetforminReduces hepaticAdverse hepatic effectsguanidesglucoseLactic acidosisproductionUnwantedImprovesUnwantedImprovesgastrointestinal effectssensitivity toinsulinGlu-AcarboseReduces glucoseWorks only after mealscosidaseabsorption fromGI side effectsinhibitorsgutThia-TroglitazoneReduce insulinNot effective in 25% ofzoli-Rosi-resistancepatientsdinedionesglitazoneRequire frequent liverPia-function testsglitazoneHave very long onset ofactionCause weight gain
As is apparent from the above table, there are disadvantages to each of the currently available agents for use in the treatment of diabetes. Accordingly, there is a continuing interest in the identification and development of new agents, particularly orally administered, water-soluble agents that can be used for the treatment of diabetes.